Abstract
(Englisch)
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High potency 'emergency' foot-and-mouth disease (FMD) vaccines will protect pigs against aerosol challenge infection within 4 days post-vaccination. The main objective of this project was to scrutinize the effector mechanisms involved in this early protection. Following 'emergency' vaccination, specific antibody responses were not detected until 7 days post-vaccination. Analysis of the cytokine profiles demonstrated that the specific defences were not restricted to Th1-like or Th2-like. The response was regulated by an adherent population of myeloid cells, which appeared to interplay with the stimulatory myeloid cells (antigen presenting cells - APC) in controlling the level of specific lymphoproliferation.
These results were also related to the animal haplotype. The SLA class I (SLA-I) haplotypes H01, H02, H03, H04, H07, H08, H11, H14, H15, H16, H24, H28, H67, DC80 and DC85 were detected. Two Swiss breeding sows were natural homozygotes for H07 or H28. They were also SLA-II DQB07 or DQB28 homozygotes. In addition, SLA-II DQB types DQB04, DQB07, DQB14, DQB16, DQB28, DQB85 and DQB86 were detected. Certain of these haplotypes have now been defined as linking to potential low responder and high responder animals. Nevertheless, early post-vaccination, the levels of systemic antibody were inadequate to explain the protection. There was no detectable phenotypic difference amongst the sub-populations of immune cells, compared with non-vaccinated controls. Monocytic cell differentiation was found. Elevated phagocytic and endocytic activities as well as endosomal/lysosomal acidification were more macrophage-associated, whereas higher accessory activity for efficient stimulation of antigen-specific lymphocytes was more monocyte-associated. The greater capacity of the macrophage to phagocytose FMDV would be an important event in the early protection. In the absence of specific antibodies, relating to the situation early post-vaccination, there was a slow uptake of the virus, but the loss of virus infectivity and viral antigen took over 24h. Initially, the virus remained on the cell surface, then became internalised. This internalised virus also remained infectious, in the absence of virus replication. Both surface and internalised infectious virus could be released from the macrophages for at least 10h p.i., probably by exocytosis. The virus interfered with macrophage protein synthesis, which may have impaired degradation of the virus. Such characteristics would permit macrophages to carry infectious FMDV to various body sites, where it could be released to infect other cells for replication. Consequently, the early events post-vaccination, leading to protection, must alter monocytic cells to reverse virus survival.Further analyses of these innate defences early post-vaccination found no evidence for increased natural opsonin activity, acute phase protein activity, or the inflammatory cytokines IL-1 and TNF. In contrast, IL-6, IL-8 and IL-12 were induced, indicative of elevated monocytic cell activity. Increased chemotactic activity of monocytes and granulocytes - the main cellular effectors of innate defences - was identified, and only with the vaccinates. Plasma from the vaccinates also had increased chemotactic properties, suggesting early recruitment of phagocytes into the tissues, and their activation to be potent effectors.
Conclusions
Following emergency vaccination of pigs against FMDV, animals can be protected from aerosol challenge within 4 days, and these responses remain protective for at least 7 months. Specific anti-virus antibodies are detectable from 7 days. Haplotyping demonstrated that particular haplotypes might relate to the rate at which the immune response develops, and certainly the peptide antigens which can be recognised as immunogenic.
Both innate and acquired immune mechanisms are involved in the efficient response following emergency vaccination against FMDV. Enhancement of innate responses is essential for the early protection. This is important due to the observation that macrophages have the potential to carry infectious FMDV to different sites in the body, where it could be released to infect other cells for replication. The enhanced innate response early post-vaccination was seen in terms of cytokine stimulation (IL-6, IL-8 and IL-12) and enhanced chemotactic activity These effects were due to the vaccine, not the adjuvant. These results will be taken into consideration in the future development of vaccines against FMDV.
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